Inflammatory bowel disorders or diseases (IBD) encompass a spectrum of overlapping clinical diseases that appear to lack a common etiology. IBD, however, are characterized by chronic inflammation at various sites in the gastrointestinal (GI) tract. Illustrative IBD are regional enteritis (or Crohn's disease), idiopathic ulcerative colitis, idiopathic proctocolitis, pouchitis and infectious colitis. Symptoms of IBD may include persistent diarrhea, abdominal pain, fever, weight loss, joint pain, skin lesions and general fatigue. The inflammatory conditions of ulcerative colitis are confined to the colon, unlike Crohn's disease which can involve any portion of the intestinal tract.
Current treatment for IBD includes oral, IV and colonically administered corticosteroids and oral and colonically administered 5-aminosalicylic acid (Edsbacker et al., Gastroenterology 104:A695 (1993); Greenberg et al., NEJM 317:1625-29 (1987). cyclosporin is another treatment for IBD, but this is limited to oral administration since colonic administration was not efficacious; (Gastroenterology 1994, 108:1429-1435).
Several types of colonic drug delivery systems are currently available, including enemas (Sutherland et al., Med. Clin. North Amer., 74:119 (1990)); rectal foams (Drug Ther. Bull., 29:66 (1991)); and delayed oral release formulations in the form of enteric-coated capsules which disintegrate at pH7 in the terminal ileum (Schroeder et al., NEJM, 317:1625 (1987)).
Carbomers have been shown to promote gel formation with mucin monomers from both gastric and colonic mucus (Pullan et al., Gut, 34:676-9 (1993)), and they may also inhibit fecal protease activity, which is responsible for mucolysis and solubilization of the adherent layer of mucus gel. This inhibition of mucolysis strengthens the colonic mucus barrier, which is deficient in ulcerative colitis and may play a role in its pathogenesis (Hutton et al., Clin. Sci., 78:265-71 (1990)).
Studies have suggested that an important epidemiologic link exists between ulcerative colitis (UC) and a patient's smoking history. Several investigators have reported that the prevalence of UC in non-smokers is higher than in current smokers. In addition, studies have suggested that ex-smokers are at even greater risk than life-time smokers for developing UC. It further appears that lifetime non-smokers exposed in childhood to passive tobacco smoke have a greater risk of developing ulcerative colitis than non-exposed lifetime non-smokers.
The observations that active colitis improves with smoking has led to investigational use of nicotine as a therapeutic agent. Since it would be unethical to ask patients to take up smoking, the nicotine was administered as polacrilex gum and a transdermal patch for the treatment of colitis (Roberts et al., Br. Med. J. 285:440 (1982); Srivastava et al., Eur. J. Gastro. & Hepat. 3:815-6 (1991); Pullman et al, The New England Journal of Medicine, March 1994, 811-815; Thomas et al, The New England Journal of Medicine, April 1995, 988-992). The great advantage of these routes of administration was like smoking a cigarette, the dose could be careful controlled and this was essential because of the highly addictive and toxic nature of nicotine. For example if the patient was feeling unwell, the patch could simply be removed. This was not an option with i.v, and oral formulations.
However, long term nicotine administration by way of polacrilex gum or transdermal patch proved to have limitations due to systemic side effects, as well as those inherent to the specific administration vehicles. For example, nicotine administered as chewing gum results in variable absorption and a wide range of plasma nicotine levels. Long term use of the transdermal patch is limited by a relatively high rate of dermatologic side effects. General side effects of nicotine administration reported in the aforementioned papers included nausea, vomiting, headaches, insomnia, somnolence, diaphoresis, pre-syncope and tremor, and in many cases forced the patient to withdraw from the treatment. In particular Pullman reported that three patients withdrew from treatment within three days because of intolerable side-effects, two more withdrew later, and the dosage had to be reduced in a further six patients. Thomas et al also reduced the dose of nicotine in the patch from 25 mg to 15 mg daily in an attempt to reduce the side effects to a tolerable level, but in the process lost the efficacy.
Thus, a need exists for a safe and effective method of treating IBD.